Antiepileptic and Anticonvulsant Drugs Antiepileptic and Anticonvulsant Drugs Dept. of Pharmacology, School of Medicine, Zhejiang University [email protected]

Antiepileptic and Anticonvulsant Antiepileptic and Anticonvulsant DrugsDrugs

张纬萍

Dept. of Pharmacology, Dept. of Pharmacology, School of Medicine, Zhejiang UniversitySchool of Medicine, Zhejiang University

[email protected]@zju.edu.cn

Seizure

•Epilepsy is not a single entity; it is a family of different Epilepsy is not a single entity; it is a family of different

recurrent seizure disorders that have in common the recurrent seizure disorders that have in common the

sudden, excessive and disorderly discharge of central sudden, excessive and disorderly discharge of central

neurons. neurons.

•This results in abnormal movement or perceptions that This results in abnormal movement or perceptions that

are of short duration but that tend to recur.are of short duration but that tend to recur.

Local excitatory

Abnormal high frequency discharging

Abnormal spreading

Brain malfunctionAccompanied with abnormal EEG

发病率高；

突发性，不可预测；

不可根治，需终身服药

Classification of epilepsyClassification of epilepsy

International Classification of Epileptic Seizures:Partial Onset Seizures （局限性发作）

Simple Partial （单纯局限性）

Complex Partial （复合性局限性）

Partial Seizures with secondary generalization

（局限性发作继发全身强直阵挛性发作）

• Partial seizures with dyscognitive features

• Partial seizures without dyscognitive features

International Classification of Epileptic Seizures: Primary Generalized Seizures

Absence (Petit Mal) （失神性发作 / 小发作）

Myoclonic （肌阵挛性发作）

Generalized Tonic+Clonic

（全身强直阵挛性发作）

http://www.uwo.ca/cns/resident/pocketbook/pictures/3-hz-s-w.jpg

The pathways for seizure propagation in partial seizures and primary generalized seizures

Origin of a surface epileptic discharge

强直性发作阵挛性发作

发作后抑制表面脑电图

细胞外记录

细胞内记录PDS ： paroxysmal depolarization shift 阵发性去极化漂移

Sodium InfluxCalcium Influx

Chloride Influx

PDS

Surface Spike

K efflux

Seizures are generated by groups of neurons which depolarizing synchronously

Epileptic neurons generate Paroxysmal Depolarizing Shift ( 阵发性去极化飘移 , PDS)

During a PDS, there is the repetitive activation of key ion channels.

These ion channels represent opportunities to prevent or terminate seizures.

Mechanisms of antiepileptic drugsMechanisms of antiepileptic drugs

ElectrophysiologicalElectrophysiological Inhibiting excessive dischargesInhibiting excessive discharges Inhibiting spread of dischargesInhibiting spread of discharges

MolecularMolecular Potentiating GABA neuronal functionsPotentiating GABA neuronal functions Inhibiting excitatory neuronal functionsInhibiting excitatory neuronal functions Modulating NaModulating Na++, Ca, Ca2+2+, K, K++, Cl, Cl- - channel fuctichannel fucti

onsons

Molecular targets for anti-seizure drugs at the excitatory, glutamatergic synapse.

兴奋性

Molecular targets for anti-seizure drugs at the inhibitory, GABAergic synapse.

抑制性

AntiepilepticAntiepilepticdrugsdrugs

Focus formation and epileptic attackFocus formation and epileptic attack

Focus shiftFocus shift

Refractory epilepsyRefractory epilepsy

Imbalance of excitation and inhibitoryImbalance of excitation and inhibitory NaNa++ 、、 CaCa2+2+ 、、 NMDANMDA 、、 KK+ + 、、 ClCl-- 、、 GABAGABA

SpreadingSpreading

A.A. Antiepileptic drugsAntiepileptic drugs

Special drugsSpecial drugs

Phenytoin Sodium Phenytoin Sodium 苯妥英钠苯妥英钠 , , 大仑大仑丁丁

CO

N

N

HC6H5

C6H5

NaO

1. 1. Pharmacological effects and the mechanismPharmacological effects and the mechanism

(1) Effects(1) Effects

— — Inhibiting spread ofInhibiting spread of abnormal discharges abnormal discharges

— — Not on the happening of abnormal dischargeNot on the happening of abnormal discharge


苯妥英钠苯妥英钠

1. Pharmacological effects and the mechanism

(2) Mechanism

— Blocking Na+ channel in inactive state

— Inhibiting L- and N-type Ca2+ channel

(but not T-type Ca2+ channel )

— Calmodulin kinase activity

Neurotransmitter release (NE, 5-HT, DA etc.)

— Block posttetanic potentiation (PTP) formation


2. Clinical uses

(1) Anti-epilepsyGrand mal, status epilepticus; Partial seizures (simple and complex); Ineffective for petit mal (absence seizures)

失身小发作(2) Trigeminal ( 三叉神经疼 ) and related

neuralgia ( 神经疼 )

(3) Anti-arrhythmia


Larger doses: non-linear kinetics （ > 10 g/ml ）

Half life = 24 hours

Therapeutic range = 10-20 ug/ml

Levels above 20 cause ataxia ( 共济失调 ) and nystagmus （眼球震颤）

Hepatic metabolism

CYP3A enzyme pathway

CYP3A antagonists will raise phenytoin levels

Necessary to monitor plasma concentrations

Initially linearPsuedo first order

A.A. Antiepileptic drugsAntiepileptic drugs3. 3. ADMEADME

4. 4. Adverse effectsAdverse effects

(1) Local reactions(1) Local reactions GI reactions; gingival hyperplasiaGI reactions; gingival hyperplasia

(2) CNS reactions(2) CNS reactions Particularly in the cerebellum and vestibular systems: Particularly in the cerebellum and vestibular systems:

nystagmus (nystagmus ( 眼球震颤眼球震颤 ), ataxia (), ataxia ( 共济失调共济失调 ), ), etc.etc.

Behavioral changes: confusion, hallucination, comaBehavioral changes: confusion, hallucination, coma

(3) Hemological reactions(3) Hemological reactions Megaloblastic anemia (affect the metabolism of folic Megaloblastic anemia (affect the metabolism of folic

acid)acid)


(4) Allergic reactions(4) Allergic reactions Skin reactions; blood cell abnormality (including Skin reactions; blood cell abnormality (including

thrombocytopenia, agranulocytosis);thrombocytopenia, agranulocytosis); hepatic toxicity; hepatic toxicity; ect.ect.

(5) Skeletal reactions(5) Skeletal reactions Osteomalacia (Osteomalacia ( 骨质疏松骨质疏松 ) by increase vitamin D ) by increase vitamin D

metabolism and calcium absorption (inducer)metabolism and calcium absorption (inducer)

(6) Others(6) Others Birth defects, Birth defects, hirsutism, etchirsutism, etc


5.5. Drug interactions Drug interactions （蛋白结合、代谢）（蛋白结合、代谢）

(1) Increases plasma concentrations of drugs by (1) Increases plasma concentrations of drugs by displacement of plasma protein binding displacement of plasma protein binding (salicylates)(salicylates)

(2) Drug metabolizing enzyme (2) Drug metabolizing enzyme inhibitorinhibitor decrease the decrease the metabolismmetabolism of phenytoin of phenytoin (isoniazid(isoniazid 异烟肼异烟肼 , , chloramphenicolchloramphenicol 氯霉素氯霉素 ))

(3) Drug metabolizing enzyme (3) Drug metabolizing enzyme inducer inducer increase the increase the metabolismmetabolism of phenytoin of phenytoin (phenobarbital, (phenobarbital, carbamazepine)carbamazepine)

(4) Phenytoin enhances the metabolism of corticosteroids (4) Phenytoin enhances the metabolism of corticosteroids and vitamin Dand vitamin D


Phenobarbital Phenobarbital 苯巴比妥苯巴比妥


C2H5

CO

NH

NH

CO

CO

C

C6H5

Sedative and hypnoticSedative and hypnotic effect effect Inhibiting both formation and spread of discharges.Inhibiting both formation and spread of discharges. Postsynaptic Postsynaptic ClCl-- influx influx Presynaptic Presynaptic Ca Ca2+2+ influx influx neurotransmitter release neurotransmitter release

(NE, ACh, Glu, etc.) (NE, ACh, Glu, etc.) Effective for grand mal , status epilepticus, partial Effective for grand mal , status epilepticus, partial

simple seizures.simple seizures.

Drugs acting at the chloride channel

Benzodiazepines Binds to specific

receptors

Phenobarbital Binds to barbiturate

specific receptor

Valproate Decreases GABA

degradation in presynaptic terminal


苯巴比妥

苯二氮卓类

丙戊酸钠

Block T-type CaBlock T-type Ca2+2+ channel channel Block NaBlock Na++-K-K++-ATPase-ATPase Inhibit cerebral metabolism and GABA tInhibit cerebral metabolism and GABA transaminaseransaminase Effective for peptit malEffective for peptit mal Combined with phenobarbitalCombined with phenobarbital

Ethosuximide Ethosuximide 乙琥胺乙琥胺


Valproate sodium Valproate sodium 丙戊酸钠丙戊酸钠


Broad spectrum

Inhibiting spread of discharges but not formation

Increases GABA levels via

inhibiting GABA tGABA transaminase,ransaminase,

GABA transport,GABA transport, Glutamate Glutamate decarboxylasedecarboxylase

Inhibit Na+ and L-type Ca2+

Enhance K+ ?

GI side effects Tremor Hepatitis Pancreatitis Serious neural tube and

cardiac defects in fetus in 1%

Blocks Na+ and Ca2+ channels

Enhance GABA Effective against

psychomotor seizures, and grand mal

Effective for mania, depression, and neuralgia

Like phenytoin, metabolized by CYP3A pathway (an inducer)

Need titration up!

Safety and Toxicity Dose dependence-double vision,

ataxia

rash 5-10%

rare marrow suppression

rare hepatitis

frequent hyponatremia/Water intoxication (Dose dependence)

fetal malformations

Carbamazepine Carbamazepine 卡马西平卡马西平


N

CONH2

Other antiepileptic drugsOther antiepileptic drugs

Primidone Primidone 扑米酮扑米酮：： analogues of phenobarbital, used analogues of phenobarbital, used for phenobarbital- and phenytoin-ineffective patientsfor phenobarbital- and phenytoin-ineffective patients

Mephenytoin Mephenytoin 美芬妥英美芬妥英 ,, Ethotoin Ethotoin 乙苯妥英乙苯妥英：： analogues analogues of phenytoinof phenytoin

Diazepam Diazepam 地西泮地西泮 : : status epilepticus (status epilepticus (i.v.i.v.)) Nitrozepam Nitrozepam 硝西泮硝西泮 ,, Clonazepam Clonazepam 氯硝西泮氯硝西泮：： peptit malpeptit mal

Lamotrigine Lamotrigine 拉莫三嗪拉莫三嗪


Other antiepileptic drugsOther antiepileptic drugs

OxarbazepineOxarbazepine （奥卡西平）：（奥卡西平）： similar as carbamazepine but similar as carbamazepine but weakerweaker

AntiepilepsirineAntiepilepsirine （抗痫灵）（抗痫灵） : : broad spectrum, esp.broad spectrum, esp. grand mal

Lamotrigine Lamotrigine 拉莫三嗪：拉莫三嗪： NaNa++ channel antagonist. Effective channel antagonist. Effective against both partial and generalized epilepsyagainst both partial and generalized epilepsy

FlunarizineFlunarizine 氟桂利嗪氟桂利嗪 : Inhibit L- and T-type Ca: Inhibit L- and T-type Ca2+2+ channel. channel. broad spectrumbroad spectrum

TopiramateTopiramate 托吡酯：托吡酯： Blocks AMPA+kainate receptorsBlocks AMPA+kainate receptors

Also blocks Also blocks NaNa++ and Ca and Ca2+2+ channelschannels


卡马西平

苯妥英钠丙戊酸钠

拉莫三嗪

丙戊酸钠

乙琥胺

二甲双酮

丙戊酸钠

苯二氮卓类

巴比妥类

Common toxicity of antiepileptic drugs:Common toxicity of antiepileptic drugs:

CNS reactionsCNS reactions

Hemological reactionsHemological reactions

Hepatic toxicityHepatic toxicity

TeratogenicityTeratogenicity （致畸）（致畸）


Teratogenicity

All AED's cause fetal malformations in at least 6% of infants.

Highest risk with phenytoin, valproate, phenobarbital, and carbamazepine (Class D drugs)

Folate supplementation prevents neural tube defects.

Principals of antiepileptic drug usesPrincipals of antiepileptic drug uses1. Choice of drugs1. Choice of drugs

(1) Grand mal / Partial(1) Grand mal / Partial ：： Phenytoin, Carbamazepine, PhenobarbitalPhenytoin, Carbamazepine, Phenobarbital Primidone, Valproate sodium

(2) Peptit mal:(2) Peptit mal: EthosuximideEthosuximide

Clonazepam, Valproate sodium

(3) Psychomotor(3) Psychomotor ：： Carbamazepine, PhenytoinCarbamazepine, Phenytoin

(4) Status epilepticus(4) Status epilepticus ：： Diazepan (i.v.)Diazepan (i.v.)

Phenytoin (i.v.), Phenobrbital (i.m.)


2. Dosage2. Dosage ：： small small larger doses; larger doses; dose individualization; dose individualization; plasma concentration monitoring if necessaryplasma concentration monitoring if necessary

3. Usage3. Usage ：： drug combinationdrug combination

4. Withdrawal4. Withdrawal ：： gradually and slowlygradually and slowly


1. Effects ： central depression; vasodilatation, BP ; relaxing skeletal muscles

2. Uses ： convulsion ； hypertension crisis

3. Adverse effects ：depression of respiratory and vasomotor centers,

antagonized by calcium preparations (i.v.)

Magnesium Sulfate 硫酸镁

B.B. Anticonvulsant drugsAnticonvulsant drugs

Other anticovulsant drugsOther anticovulsant drugs

Sedative-hypnotic drugsSedative-hypnotic drugs

B.B. Anticonvulsant drugsAnticonvulsant drugs

Drugs which primarily affect K+ channel

Levetiracetam左乙拉西坦

High Potency->75% reduction in seizures in over 20% of refractory patients

Few side effects except: Fatigue Depression and Psychosis

leading to discontinuation in 7%.

White et al Neurology 2003

Mechanism -Multiple Blocks AMPA+kainate

receptors Also blocks sodium and

CA channels Potentiate GABA

transmission Effective against both partial

and generalized epilepsy Excreted primarily in urine Start at 25 mg/day…titrate to

300-500/day

Behavioral /Cognitive problems common

Low risk of rash Causes weight loss Relatively safe, Class C in

pregnancy High Potency

> 75% reductions in over 20% of refractory patients

Drugs which affect Kainate and AMPA receptors

Zonisamide

Topiramate

Anti-epileptics (AEDs)

Note: All of the following drugs have multiple mechanisms of action (primary mechanisms include blockade of voltage gated Na+ channels, enhancement of GABAergic neurotransmission, and inhibition of glutamatergic neurotransmission)

Older AED’s phenytoin voltage gated Na+ channel blocker

carbamazepine voltage gated Na+ channel blocker valproate/valproic acid GABA metabolism inhibitor phenobarbital allosteric GABA A agonist

Newer AED’s oxcarbazepine voltage gated Na+ channel blocker lamotrigine voltage gated Na+ channel blocker topiramate glutamate receptor antagonist; voltage gated Na+ channel blocker levetiracetam multiple actions gabapentin Ca2+ channel blocker zonisamide glutamate receptor antagonist; Na+ and T-type Ca+2+ channel blocker lorazepam (I.V.) for status epilepticus allosteric GABA A agonist

inhibition is use-dependent; limits ability of neurons to fire at high frequency. . maintains Na+ channel in inactivated state and slows rate of recovery; no change in spontaneous activity or firing at slow rate)

Anti-Epileptic Drug’s Effective as Monotherapy (Single Agent)

Partial (Localization Related)

Older AED’s Phenytoin (苯妥英钠 ) Carbamazepine （卡马西平） Valproate （丙戊酸钠）

Newer AED’s Oxcarbazepine （奥卡西平） Lamotrigine （拉莫三嗪） Topiramate （托吡酯）

French et al Neurology 2004

Bold= new generation AED

Generalized

Valproate （丙戊酸钠） (GTC and absence)

Topiramate （托吡酯） (GTC)

Lamotrigine （拉莫三嗪） (absence)

French et al Neurology 2004

New AED’s effective as adjunctive treatment for refractory epilepsy

Partial

Topiramate Levetiracetam Pregabalin Zonisamide Oxcarbazepine

Lamotrigine Gabapentin TiagabineAbove all have level I, randomized clinical

trials, or A or B evidence, AAN guidelines 2004

Generalized

Topiramate Levetiracetam Lamotrigine

Data from randomized placebo controlled trials

Drugs in red are generally considered high potency

Increased expression of ABC transport in Increased expression of ABC transport in epilepsyepilepsy

TransportersTransporters

耐药癫痫大鼠耐药癫痫大鼠 P-gpP-gp 表达增加表达增加

抗癫痫药敏感大鼠抗癫痫药敏感大鼠抗癫痫药耐药大鼠抗癫痫药耐药大鼠

ControlControl 耐药癫痫大鼠耐药癫痫大鼠

P-gpP-gp 抑制剂增强抗癫痫药抑制剂增强抗癫痫药 OxarbazepineOxarbazepine （（ OXC, OXC, 奥奥卡西平）作用及延长癫痫病人入院间隔时间卡西平）作用及延长癫痫病人入院间隔时间

P-gpP-gp 基因敲除及其抑制剂增加脑内抗癫痫药浓度基因敲除及其抑制剂增加脑内抗癫痫药浓度

Contribution of CYPs to drug metabolism

CYP Enzymes

(from Guengerich 2003)

抑制剂

诱导剂

底物

AEDs and Hepatic CYP450 Interactions

Valproic acid CYP2C inhibitor (inhibits phenobarbital, phenytoin metabolism)

Phenytoin CYP inducer (3A4 and 2C); metabolized by 2C9

Carbamazepine CYP inducer (CYP inducer (3A4 and 2C); metabolized by 3A4. . . induces its own metabolism

Phenobarbital CYP inducer (3A4 and 2C)

Induction – increase in amount of enzyme protein, resulting in an increase in the rateof metabolism of the affected drug

Inhibition – competition at the enzyme site that results in a decrease in metabolismof the affected drug

Drugs Treating Parkinson Disease Drugs Treating Parkinson Disease and Alzheimer Diseaseand Alzheimer Disease

Parkinson’s disease (PD)Parkinson’s disease (PD)

RigidityTremorBradykinenesiaPostural instability(propulsion, retropulsion).

Tremor:Tremor: one of the one of the common symptoms of PDcommon symptoms of PD

黑质黑质 -- 纹状体通路纹状体通路

中脑中脑 -- 边缘边缘 // 皮层通皮层通路路

结节结节 -- 漏斗通漏斗通路路 Substantia nigro -Substantia nigro -

striatum dopaminergic striatum dopaminergic pathwaypathway is involved in is involved in PD pathogenesisPD pathogenesis

Parkinson diseaseParkinson disease

Dopaminergic neuron Dopaminergic neuron degeneration in degeneration in substantia nigro and substantia nigro and striatumstriatumNormalNormal

DopamineDopamine

AcetylcholineAcetylcholine

Abnormal balance of DA/ACh neuronal functions Abnormal balance of DA/ACh neuronal functions in extrapyramidal system of Parkinson diseasein extrapyramidal system of Parkinson disease

LevodopaLevodopa

Muscarinic Muscarinic antagonistsantagonists

NormalNormal

Parkinson diseaseParkinson disease

(-)

injuredinjured

relatively relatively potentiatedpotentiated

(-) (-)

Tyrosine

TH

DOPA

Dopamine Decarboxylase

Dopamine

DBH

Norepinephrine

MAO-Bmetabolisms

MAO-Ametabolisms

DA receptors

Treatment I: Increase dopamine

Different approaches include:

I. increases in dopamine synthesis capacity

II. direct activation of post-synaptic receptors

III. inhibition of dopamine metabolism

IV. alteration of the interaction/balance with other

neurotransmitters

V. dopamine releasers

VI. L-DOPA metabolism inhibitors

What is the desired goal of pharmacological therapies for Parkinson’s disease?

Note: All therapies treat the symptoms of the disease; none are neuroprotective and none slow the progression of the disease

NH2

OH

OH

O

OH

OH

OH

NH2

Dopamine

L-DOPA decarboxylase

L-Dopa

B6

• Striatal dopamine levels are low in PD. • Dopamine does not pass BBB and, hence, has no therapeutic effect in PD. • L-Dopa, an amino acid, the immediate precursor to

dopamine, is transported across BBB and is an effective drug for PD.

Rationale for L-Dopa Precursor Loading:

Levodopa and related drugsLevodopa and related drugsDrugs for treatment of Parkinson diseaseDrugs for treatment of Parkinson disease

(( 左旋多巴左旋多巴 ))(( 多巴胺多巴胺 ))

L-dopa is transformed to DAL-dopa is transformed to DA by dopa decarboxylase (one of by dopa decarboxylase (one of the aromatic L-amino acid decarboxylases, the aromatic L-amino acid decarboxylases, AAAD, 左旋芳香氨基酸脱羧酶 ) in both the brain and peripheral organs.) in both the brain and peripheral organs.

L-DOPA peripheral metabolism

LevodopaLevodopa1. ADME1. ADME Penetrating into the brain, transformed to DA or NE (Penetrating into the brain, transformed to DA or NE (lessless)) Distributed in peripheral tissue (Distributed in peripheral tissue (mostmost))

2. Effects and uses2. Effects and uses Parkinson disease:Parkinson disease: decreases the rigidity, tremors, and other symptoms decreases the rigidity, tremors, and other symptoms

3. Adverse effects3. Adverse effectsEarly (1) GI:(1) GI: nausea, vomiting, nausea, vomiting, etcetc..(2) CVS:(2) CVS: hypotension, arrhythmia, hypotension, arrhythmia, etcetc. . -

(1) CNS:(1) CNS: emotional depression/ psychosis; abnormal involuntary; emotional depression/ psychosis; abnormal involuntary; hallucinations; hallucinations; etcetc..

Late (1) (1) fluctuation of response: end of dose/“wearing off” periods; on/off fluctuation of response: end of dose/“wearing off” periods; on/off periods (sudden loss of symptom control, akinesia)periods (sudden loss of symptom control, akinesia) ..(2) (2) dyskinesia (dyskinesia ( 运动运动障碍，障碍， after years of chronic L-DOPA, up to 80%, Involuntary after years of chronic L-DOPA, up to 80%, Involuntary movements: movements: chorea( 舞蹈症 ), ballismus( 投掷症 ), athetosis( 手足徐动症 ), dystonia( 肌张力失常 ), myooclonus( 肌阵挛 ), and tremor

Drugs for treatment of Parkinson diseaseDrugs for treatment of Parkinson disease

Carbidopa ( 卡比多巴卡比多巴 )a peripheral decarboxylase inhibitor reduces peripheral metabolism of L-DOPA, increases L-DOPA bioavailability, can not cross BBB;decreases its adverse effects by allowing lower L-DOPA dosages to be used.The combination of L-DOPA & carbidopa, is called Sinemet™. (L-DOPA t1/2 ~ 1.5 h)

HO

O

CH3

NH NH2

OH

OH

Carbidopa

3-O-methyl- DOPA

Periphery CNS

L-DOPA

dopamine

BBB

COMT

AAAD

L-DOPA

dopamine

AAAD

MAO

Pyridoxal 5- phosphate

Levodopa aloneLevodopa alone

Levodopa Levodopa

++

CarbidopaCarbidopa

Dopamine Synthesis and Storage

Without With COMT Inhibitor

FDOPA -/+ COMT Inhibitor: 2 FDOPA PET Studies - one individualSame dose of FDOPA, iv; plus carbidopa, po

FDOPA Uptake

Conclusion: COMT inhibitor increased brain bioavailability of FDOPA by inhibiting peripheral metabolism of FDOPA to 3-O-methyl FDOPA

FDOPA fluorodopamineAAAD COMTIn periphery: 3-O-methylFDOPAFDOPA fluorodopamineAAAD COMT

一般情况下，对 L-dopa 制剂的反应可分为 3 个阶段：

① 良好反应阶段（ 2 ～ 5 年），为用药的最初阶段，每 6 ～ 8小时或更长时间服药 1 次，可使全部症状得到平稳的缓解或改善。②中间反应阶段（ 2 ～ 3 年），此阶段中每次服药仅可引起短时间的症状改善，每个剂量的后期与下一个剂量前，有 1 个药物无作用期，称为剂末现象，此外，还可出现开关现象和反常性运动不能；这种疗效下降与黑质 DA 能神经元逐渐衰退， DA 合成、贮存进一步下降，及 DA 受体反应能力降低有关。③ 反应衰退阶段，对 L-dopa 制剂反应明显下降或根本不起反应；运动困难与致残程度更为严重；同时治疗中的一些不良反应更为明显。


Other drugsOther drugs

1. DA1. DA receptor agonist receptor agonistss1st generation agonists: (ergot derivatives)

bromocriptine* ( 溴隐亭溴隐亭 , , D2 agonist) (t1/2 ~ 12 h)

pergolide* ( 培高利特培高利特 ,, D2/D3 agonist)(t1/2 ~ 24 h)

2nd generation agonists: ropinirole (t1/2 ~ 6 h) ( 普拉克索普拉克索 ,, D2/D3 agonist)pramipexole (t1/2 ~ 8 -12 h) ( 罗平尼咯罗平尼咯 , , D2 agonist)

Can be used as monotherapy for mild parkinsonism, or combined with levodopa for advanced disease, permitting the dose of levodopa to be reduced and smoothing out response fluctuations.

• Lower incidence of dyskinesia and response fluctuation

• Some individuals develop a troubling sleep disorder, with

sudden attacks of sleep ( 突然昏睡 ) during

ordinary daytime activities

• Postural hypotension

• Dose-related psychiatric side effects (similar to L-DOPA

but may occur more frequently, especially in elderly)

• Nausea or vomiting (drugs active at chemotrigger zone

(CTZ) )

the major adverse effects of DA receptor agonists

2. MAO-B2. MAO-B inhibitor inhibitors s （（ Peripheral metabolism of catecholamines (mostly MAO-A) is unaffected. ））

decreasing DA metabolism in the CNSdecreasing DA metabolism in the CNSSelegilineSelegiline 司来吉兰司来吉兰

RasagilineRasagiline 雷沙吉兰雷沙吉兰

3. COMT inhibitors (3. COMT inhibitors (decreasing DA metabolismdecreasing DA metabolism))

CNSCNS COMT inhibitor: COMT inhibitor: ：： itecaponeitecapone 硝替卡朋硝替卡朋

peripheral COMT inhibitor:peripheral COMT inhibitor: entacaponeentacapone 恩他卡朋恩他卡朋


Drugs for treatment of Parkinson diseaseDrugs for treatment of Parkinson disease 4. 4. Amantadine Amantadine 金刚烷胺金刚烷胺

Used for mild Parkinson’s disease, as an early monotherapy

Mechanisms of action may include: release of dopamine, block DA reuptake, actions on glutamate receptors (as an NMDA-receptor antagonist)

The dose should be reduced with renal impairment.

Potential adverse effects: - CNS reactions (dizziness, anxiety, impaired coordination) - hyperkinesias( 运动亢进 ) - nausea, vomiting - others

Muscarinic antagonistsMuscarinic antagonists

Trihexyphenidyl (Trihexyphenidyl ( 苯海索，苯海索， artaneartane,, 安坦安坦 ))Benzatropine (Benzatropine ( 苯扎托品苯扎托品 ))

Decreasing CNS cholinergic functionsDecreasing CNS cholinergic functionsAdjuvant of Parkison disease treatmentAdjuvant of Parkison disease treatment


DRUG THERAPY - Summary - Summary

• Main Line Agents:• L-DOPA plus carbidopa (Sinemet®)• Dopamine receptor agonists (ropinirole)

• Lower Efficacy/Second Line or Adjuvant Agents:• Anticholinergics • Reuptake Inhibitor or releaser (amantadine)• COMT Inhibitor (entacapone)• MAO B Inhibitors (rasagiline, selegiline)

• Reserpine, which depletes brain catecholamines, induces Parkinson’s disease symptoms

• Antipsychotics (neuroleptics), that block DA receptors, ie, dopamine receptor antagonists.

• N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) is a by-product of illicit synthesis of isomeperidine. MPTP first came to medical attention because it produced symptoms similar to Parkinson’s disease.

Drug-Induced Parkinsonism

Drugs for treatment of dementia Drugs for treatment of dementia (Alzheimer and related diseases)(Alzheimer and related diseases)

Anticholinesterase drugsAnticholinesterase drugsCholinoceptor agonistsCholinoceptor agonistsNeurotrophic factor-like drugsNeurotrophic factor-like drugs

Pathological characteristics of ADPathological characteristics of AD

Atrophy of the brainAtrophy of the brain

Senile plaquesSenile plaques

Neurofibrillary Neurofibrillary tanglestangles

Senile plaquesSenile plaques and neurofibrillary tanglesneurofibrillary tangles

Regions related to neuronal injuryRegions related to neuronal injury

Importance Importance of ACh of ACh systemsystem

Mitochondrial Mitochondrial DysfunctionDysfunction

InflammationInflammation

Other FactorsOther Factors

-Amyloid-Amyloid

GlutamateGlutamate

ExcitotoxicityExcitotoxicity

Cell Damage/Cell Damage/Loss (ACh deficit)Loss (ACh deficit)

DementiaDementia

NeurofibrillaryNeurofibrillaryTanglesTangles

Pathophysiologic Hypothesis of AD

AChE

AcetylCoA

CholineACh

Presynaptic neuron

Synaptic cleft

Postsynapticneuron Acetate

CholineCholine+

+

ACh

AChE

ChAT

Normal Cholinergic Function

MR NR

MR NR

Glial cell

BuChE

BuChE

ACh

ACh = acetylcholine; AChE = acetylcholinesterase;BuChE = butyrylcholinesterase; ChAT = choline acetyltransferase; CoA = coenzyme A; MR = muscarinic receptor; NR = nicotinic receptor.

Adapted from Adem, 1992.

Anticholinesterase drugs Tarcrine 他克林 :

Easy to pass BBB; Decrease AChE 70%; activate M and N receptors (especially M receptor); Enhance the release of ACh (throught M receptor). Induce hepatic toxicity.

Galantamine 加兰他敏 : similar to tarcrine, except without hepatic toxicity and high specific to neuron AChE.

Huperzine 哈伯因（石杉碱甲） : a high selective AChE inhibitor; improve memory and recognization.

Metrifonate 美曲磷脂 : the first AChE inhibitor; Increase central DA and NE; Decrease the red blood cell AChE 52%.

Drugs for treatment of dementiaDrugs for treatment of dementia

Cholinoceptor agonists Xanomeline 占诺美林 : selective to M1 receptor; high

concentration in cortex and striatum; Has GI and CVS side effects.

Sabcomedine hydrochloride: selective to M1 receptor; safe.

Neurotrophic factor enhancer AIT 082: increase the release of neurotrophins in injured

neurons ALCAR （盐酸乙酰 L 肉碱） : protect synapse and

increase nurotrophins Propentofylline 丙戊茶碱 : inhibit adrenaline reuptake

and cAMP metabolize; neuroprotective effects;

Drugs for treatment of dementiaDrugs for treatment of dementia

Mitochondrial Mitochondrial DysfunctionDysfunction

InflammationInflammation

Other FactorsOther Factors

-Amyloid-Amyloid

GlutamateGlutamate

ExcitotoxicityExcitotoxicity

Cell Damage/Cell Damage/Loss (ACh deficit)Loss (ACh deficit)

DementiaDementia

NeurofibrillaryNeurofibrillaryTanglesTangles

Pathophysiologic Hypothesis of AD

Future treatment•K+channel blocker•Glutamate receptor regulator•5-HT receptor blocker

See you next class!See you next class!

Documents

Antiepileptic and Anticonvulsant Drugs Antiepileptic and Anticonvulsant Drugs Dept. of Pharmacology, School of Medicine, Zhejiang University [email protected]